SLC2A9 Is a High-Capacity Urate Transporter in Humans

作者：Mark J. Caulfield, Patricia B. Munroe, Deb O'Neill, Kate Witkowska, Fadi J. Charchar, Manuel Doblado, Sarah Evans, S. Eyheramendy, Abiodun Onipinla, Philip Howard, Sue Shaw‐Hawkins, Richard Dobson, Chris Wallace, Stephen Newhouse, Morris J. Brown, John Connell, Anna F. Dominiczak, Martin Farrall, G.M. Lathrop, Nilesh J. Samani, Meena Kumari, Michael Marmot, Eric J. Brunner, John Chambers, Paul Elliott, Jaspal S. Kooner, Maris Laan, Elin Org, Gudrun Veldre, Margus Viigimaa, Francesco P. Cappuccio, Chen Ji, Roberto Iacone, Pasquale Strazzullo, Kelle H. Moley, Chris I. Cheeseman · 发表于：PLoS Medicine · 年份：2008 · DOI：10.1371/journal.pmed.0050197 · 被引用次数：377 · 研究领域：Gout, Hyperuricemia, Uric Acid、Kidney Stones and Urolithiasis Treatments、Sodium Intake and Health

BACKGROUND: Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. METHODS AND FINDINGS: We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice varian...